Cassette and method for drug preparation and delivery

ABSTRACT

A disposable cassette for mixing an intravenous drug in a vial to a patient includes a liquid inlet for connection to a liquid supply, a first vial spike, a second vial spike and a chamber. The chamber, the first and second vial spikes, and the liquid inlet are in fluid communication with each other. A valve mechanism may be actuated to control flow between the chamber, the vial receptacles and the liquid inlet.

RELATED APPLICATIONS

The present application is a continuation of application Ser. No.10/266,997 filed Oct. 8, 2002, now U.S. Pat. No. 6,726,656 which is acontinuation of application Ser. No. 09/359,232, filed Jul. 22, 1999 nowU.S. Pat. No. 6,464,667, which is a divisional of application Ser. No.09/137,025, filed Aug. 20, 1998 now U.S. Pat. No. 6,210,361, which, inturn, is a continuation-in-part of U.S. patent application Ser. No.08/916,890 (abandoned) and Ser. No. 08/917,537 (now U.S. Pat. No.6,165,154) both of which were filed Aug. 22, 1997. All of these abovereferenced applications are hereby incorporated herein, in theirentirety, by reference.

TECHNICAL FIELD

The present invention relates to devices and methods for the preparationand delivery of intravenous drugs.

SUMMARY OF THE INVENTION

The invention is directed to a system, which may be located adjacent apatient's bed (or chair), for preparing and delivering an intravenousdrug from a vial to the patient. The system includes a liquid inlet forconnection to a liquid supply, at least (and preferably more than) onevial receptacle, and a liquid outlet for providing the intravenous drugin mixed, liquid form to the patient. Preferably, the system includes achamber having a variable volume, and a valve mechanism, which may beactuated to control flow between the liquid outlet, the variable-volumechamber, the vial receptacle and the liquid inlet. The system induceschange in the volume of the variable-volume chamber and actuates thevalve mechanism, so as to introduce liquid from the liquid inlet intothe vial and reconstitute or dilute the drug and so as to deliver thedrug to the patient. In a preferred embodiment, the liquid inlet, thevial receptacle, the variable-volume chamber, the liquid outlet and thevalve mechanism (in other words, all components that come into contactwith the liquid) are located in a disposable cassette, which may bereceived in a control unit.

In order to ensure that a powdered drug is completely reconstituted, thesystem preferably includes means for changing the chamber volume andactuating the valves so as to move the liquid repeatedly between thevial and the chamber. After the drug has been reconstituted, the systemmay cause the drug to be further diluted by providing an additionalvolume of liquid to be mixed with the drug. In a preferred embodiment,the system further includes a second chamber, and the additional volumeof liquid is mixed with the drug in the second chamber. This secondchamber preferably has a variable-volume as well. A primary purpose ofsuch a second chamber (the delivery chamber) is to deliver the drug tothe patient in precise quantities. The primary purpose of the firstchamber (the mixing chamber) is to mix and reconstitute the drugs. Toaccomplish these purposes, the mixing chamber preferably has a largervolume than the delivery chamber.

Both variable-volume chambers are preferably defined by a rigid wall anda flexible membrane. Preferably, a groove is defined in the rigid wallbetween the conduits leading into and out of the variable-volumechambers. In the mixing chamber, the groove may be made shallow adjacentthe upper conduit and wide adjacent the lower conduit, in order topromote the flow of air and liquid from the top and bottom of the mixingchamber respectively.

The disposable cassette preferably has a first valve chamber defined bya first rigid wall and a first flexible membrane, and a second valvechamber defined by a second rigid wall and a second flexible membrane;and the control unit preferably has a cam, a first actuator disposedadjacent the first flexible membrane so that movement of the firstactuator causes a change in pressure on the first flexible membrane, anda second actuator disposed adjacent the second flexible membrane so thatmovement of the second actuator causes a change in pressure on thesecond flexible membrane, wherein the cam and actuators are disposedwith respect to each other such that, as the cam is rotated, theactuators are moved. The cam is preferably shaped so that at any time atleast one actuator is urging the corresponding flexible membrane into aclosed position. The valves may be located at the inlet and outlet endsof the variable-volume chamber where the flow-rate of liquid to thepatient is measured, so that liquid cannot flow through the systemwithout being measured.

The cassette also includes, in a preferred embodiment, an outletfree-flow-prevention valve which is permanently closed to prevent flowthrough the outlet when the cassette is removed from a control unitwhich actuates the valve. Preferably, the outlet free-flow-preventionvalve includes a valve chamber defined by a rigid portion of thecassette and a membrane, wherein the membrane includes a folded portionthat extends towards the outside of the cassette, so that when anactuator from the control unit pushes the folded portion the membranecollapses into the valve chamber so as to restrict flow therethrough. Ina further preferred embodiment, the cassette includes an inletfree-flow-prevention prevention valve which is permanently closed toprevent flow through the liquid inlet when the cassette is removed fromthe control unit.

In order to ensure that all of a drug is delivered to a patient, it isimportant that all of the drug be purged from a manifold portion of thepassageways in the cassette. A preferred method of accomplishing thispurging is to further provide the cassette with an air vent in fluidcommunication with the manifold, an inlet valve controlling flow betweenthe mixing chamber and the manifold, and an air valve controlling flowbetween the air vent and the manifold. After several volumes ofmedication are moved from a vial through the manifold to the mixingchamber, air is urged from the vent through the manifold to forcesubstantially all the medication from the manifold into the mixingchamber.

Although the reconstituted drug may be delivered from the vial to thepatient, preferably fluid is drawn from the vial to the mixing chamberfor dilution to the proper concentration. Preferably, the diluted drugis then delivered from the mixing chamber to the delivery chamber, fromwhich the final dose of medication may be delivered to the patient. Asnoted above, in alternative embodiments, a separate delivery chamber isnot necessary, and the mixing chamber may deliver the diluted drugdirectly to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a system according to a preferredembodiment of the present invention.

FIG. 2 is a rear view of the cassette that may be used in the system ofFIG. 1, along with three vials attached to the cassette.

FIG. 3 is a front view of a cassette that may be used in the system ofFIG. 1.

FIG. 3A is a perspective view of the cassette of FIG. 3.

FIG. 4 is a schematic showing the fluid pathways through the cassette ofFIG. 3.

FIG. 5 is a top view of the back-plate component of the cassette of FIG.3.

FIG. 6 is a front view of the back-plate component shown in FIG. 5.

FIG. 7 is a left side view of a membrane used in thefree-flow-prevention valve of the cassette of FIG. 2.

FIG. 8 is a rear view of the membrane of FIG. 7.

FIG. 9 is a cross-sectional view of the membrane shown in FIGS. 7 and 8across lines IX—IX.

FIG. 10 is a front view of the membrane of FIG. 7.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENT

FIG. 1 shows a system for the preparation and delivery of drugsaccording to a preferred embodiment of the invention. Powdered drugs areprovided in vials 11 and are mixed by the system with a liquid providedin container 13. The system includes a disposable cassette 17, which isdisposed of between patients, and a control unit 15, which receives andcontrols the cassette, and which is used over and over. In general,liquid flows from container 13, is directed by the cassette 17 to a vial11 so as to reconstitute the powdered drug or dilute a liquid drug toits proper concentration, and then is directed by the cassette to thepatient. During periods of the drug-delivery cycle, liquid fromcontainer 13 may be directed by cassette 17 directly to the patientwithout being mixed with a drug. Premixed drugs may be delivered by thesystem from the vials to the patient and from a bag connected to a luerport (item 26 in FIGS. 2 and 3) on the cassette. The specific embodimentdiscussed herein uses separate mixing and delivery chambers. It will beappreciated by one of ordinary skill in the art, that a singlevariable-volume chamber may be used to accomplish both mixing anddelivering.

FIG. 2 shows a rear view of a cassette 17 that may be used in the systemof FIG. 1. (I.e., FIG. 2 shows the side of the cassette that faces awayfrom the control unit 15.) FIG. 3 shows a front view (i.e., thecontrol-unit side) of a cassette 17, and FIG. 3A shows a perspectiveview of the cassette. Some of the features used in this cassette 17 arealso used in the cassette disclosed in above-referenced U.S. applicationSer. No. 08/917,537 for “Cassette for Intravenous-Line Flow-ControlSystem,” and its parent, U.S. application Ser. No. 08/478,065 filed Jun.7, 1995. FIG. 2 shows three vials 11 a–11 c attached respectively tospikes 21 a–21 c. Liquid entering the cassette 17 from container 13(shown in FIG. 1) passes through port 22, and liquid going to thepatient exits the cassette through port 23. An air vent 24 permits airto be drawn into the cassette to be directed into a vial to replaceliquid leaving the vial or to be directed through the cassette'spassageways 25 in order to remove any liquid in the passageways. A luerport 26 permits a premixed drug container or alternate diluent source tobe attached to the cassette. The cassette has two pressure-conductionchambers: a delivery chamber 27 and a mixing chamber 28, both of whichare covered by a flexible membrane.

Valves 31 a–31 i control flow through the passageways 25. These valves31 a–31 i are preferably membrane-covered valves of the type shown inFIGS. 1 and 9 of U.S. Pat. No. 5,088,515. The membranes of these valves31 a–31 i may be forced into a closed position by pressure exerted bythe control unit. This pressure may be positive air pressure provided bythe control unit, or in one preferred embodiment, the pressure may beexerted by a mechanical actuator mounted in the control unit.

Valves 31 b and 32 control flow into and out of delivery chamber 27. Ina preferred embodiment, these two valves 31 b and 32 are each controlledby an actuator, and these two actuators are controlled by a single cam.The cam and the actuators are arranged so that, at all times, at leastone of valves 31 b and 32 is closed. In other words, sometimes bothvalves are closed, sometimes one valve is opened and the other isclosed, but both valves are never opened at the same time. Such anarrangement assures that liquid does not free flow through the deliverychamber.

Valve 32 controls flow from the delivery chamber 27 to the patient.Valve 32 is preferably of the type shown in FIGS. 18 and 19 of U.S.application Ser. No. 08/478,065. The membrane of valve 32 has a portionthat, when actuated by the control unit, seals off the mouth locatedwithin the valving chamber (in the same manner as valves 31 a–31 i) andanother portion that is more compliant. Valve 32 works in conjunctionwith the stopcock valve 33, so as to smooth out the delivery of fluid,in the manner described in U.S. application Ser. No. 08/478,065. Thecontrol unit includes a wheel or other mechanism for receiving androtating the cassette's stopcock valve 33.

Similar to the cassette described in U.S. application Ser. No.08/478,065, the body of the cassette 17 shown in FIGS. 2 and 3 ispreferably made from three thermoplastic layers ultrasonically weldedtogether. Most of the passageways 25 are formed between the back layerand the middle layer and are defined by the back and middle layers andchannel walls 37. In a preferred embodiment, the channel walls 37 extendfrom the middle layer and are sealingly attached to the back layer by anultrasonic weld. Some of the walls 29 between the back and middle layersdo not define passageways but merely provide structural rigidity. Thefront and middle layers define several sections 38 of the fluidpassageways, and the front and middle layers hold the membranes for thedelivery chamber 27, the mixing chamber 28 and the valves 31 a–31 i, 32.Walls 39 are provided on the front side of the middle layer to permiteasier ultrasonic welding of the channel walls between the back andmiddle layers.

Each of the vial spikes 21 a–21 c may be provided with a spike cap 21′to keep the cassette and spikes safe and sterile during storage andhandling. Similarly, the luer port 26 may be provided with a cap 26′ tokeep the cassette sterile.

The inlet port 22 and the outlet port 23 are respectively provided withfree-flow-prevention valves 34 and 35, which are automatically closed bythe control unit when the door holding the cassette is opened. Thesefree-flow-prevention valves are discussed in greater detail below inconnection with FIGS. 7–10.

FIG. 4 is a schematic showing how the valves control the flow of fluidthrough the cassette shown in FIGS. 2 and 3. In a typical application,the inlet 22 of the cassette is attached to an IV solution source (item13 in FIG. 1), the luer port is connected to a liquid medicine supply,and each of the spikes (items 21 a–21 c in FIG. 3) may be attached to avial 11 a–11 c containing a powdered drug that must be reconstituted bythe IV solution source or containing a liquid drug that may or may notneed to be diluted before being delivered to the patient.

Dilution is performed by pulling liquid from the solution source (item13 in FIG. 1) and the vial to the mixing chamber in the appropriateproportions. Of course, it is important that the drugs be diluted thecorrect amount so as to avoid sending to the patient a drug solutionthat is too concentrated or too diluted. To ensure the correct amount ofdilution, liquid from the IV solution source is measured in the deliverychamber 27 before being sent to the mixing chamber.

An example of a typical drug-delivery cycle first prepares the drug fromvial 11 a for delivery to the patient, then the drug from vial 11 b,then the drug from vial 11 c and then the liquid drug provided throughthe luer port 26. (Of course, variations of this drug-delivery cycle maybe implemented.) To implement such a cycle, the control unit (item 15 ofFIG. 1) actuates the membrane-based valves 31 a–31 i and 32, as well asthe stopcock valve 33.

After the cassette has been primed, valves 31 a and 31 b are opened(with all the other membrane-based valves 31 c–31 i, 32 kept closed),and the control unit applies a negative pressure for a specified amountof time against the membrane of the delivery chamber 27, so as to drawliquid from the IV solution source into the delivery chamber. In apreferred embodiment, the rigid wall defining the variable-volumedelivery chamber includes a bulge or other irregularity to make themembrane defining the delivery chamber less stable when the chamber isat its lowest volume; this instability makes it easier for the membraneto be pulled away from the rigid portion.

After a sufficient amount of liquid has been introduced into thedelivery chamber 27, valve 31 a is closed, and the control unit uses,for example, the bubble-detection method taught in U.S. patentapplication Ser. No. 08/477,330 filed Jun. 7, 1995 (which isincorporated herein by reference) to determine whether there is any airin the delivery chamber 27. If there is any air bubble in the deliverychamber 27, the application of pressure by the control unit against thedelivery chamber's membrane may be used to force the air bubble to theIV solution source (through port 22), the air vent 24 (if it is capableof venting air in two directions) or the mixing chamber; to which ofthese three locations the bubble is directed depends on whether valve 31a, valve 31 g or valve 31 h is opened by the control unit.

After any bubble has been eliminated from the delivery chamber 27, thecontrol unit takes a measurement of how much air is in the space definedby the control unit outside of and adjacent to the delivery chamber'smembrane; in a preferred embodiment, the control unit uses an acousticvolume measurement system, such as that taught in U.S. Pat. No.5,349,852 (which is also incorporated herein by reference). If thecombined total volume of the delivery chamber and the space adjacentthereto is known, the amount of liquid in the delivery chamber may bedetermined by subtracting the measured volume of air from the knowntotal volume.

Before any drugs are mixed, it may be desired to deliver some IVsolution to the patient in order to establish flow through the line fromthe outlet 23 to the patient and through the patient's vein. In order todeliver liquid from the delivery chamber 27 to the patient, valve 32 isopened while the stopcock valve 33 is controlled and while pressure isapplied to the delivery chamber's membrane by the control unit. (Thevalve 32 and stopcock valve 33 may be controlled in the manner describedin U.S. application Ser. No. 08/478,065, referenced hereinabove). Thestopcock valve and pressure may be adjusted to control the rate of fluiddelivered.

After an amount of fluid is delivered from the delivery chamber 27 tothe patient, the volume of liquid delivered to the patient may bedetermined by taking another measurement of the volume of air defined bythe control unit adjacent to and outside of the delivery chamber.Subtracting the volume of air measured before any liquid has beendelivered from the volume of air measured after the liquid has beendelivered provides the volume of liquid delivered to the patient. Byusing the acoustic volume measurement system of U.S. Pat. No. 5,349,852,and opening valve 32 and stopcock valve 33 at the same time the amountof liquid delivered may be tracked in real time as it is beingdelivered.

After the amount of liquid delivered from the delivery chamber 27 hasbeen determined, the delivery chamber may be refilled by closing valve32, as well as valves 31 c–31 i, and then opening valves 31 a and 31 b.The control unit again applies a negative pressure against the deliverychamber's membrane so as to draw liquid from the IV solution source intothe delivery chamber 27. This additional IV solution may also bedirected straight to the patient again in the manner describedhereinabove, or it may be used in the admixture process in the mixingchamber. In a preferred embodiment, the volume of liquid in the deliverychamber is split, with a portion being delivered to the patient and theremainder being sent to the mixing chamber, where the liquid is used toreconstitute the drugs in the vials.

In order to reconstitute a powdered drug, liquid is introduced into thevial containing the powdered drug. With the cassette embodiment depictedin FIGS. 2–4, a mixing chamber 28 separate from the delivery chamber 27is used to mix the IV solution with the drug. As noted above, it will beappreciated that, in an alternative embodiment, a single chamber may beused. In order to reconstitute the drug properly, it is important thatthe correct amount of IV solution be introduced into the vial.Typically, the correct volume of IV solution necessary to reconstitutethe drug is more than the volume of the delivery chamber 27 (which in apreferred embodiment is 4 ml).

There are two basic types of drug preparation cycles: those drugs whichcome in powdered form requiring reconstitution, and those coming inliquid form which may or may not need dilution.

In a typical reconstitution cycle, IV solution is first introduced fromthe IV solution source into the delivery chamber 27. The control unitthen determines whether there are any air bubbles in the deliverychamber 27 and, if there is none, makes a measurement of the volume ofair defined by the control unit adjacent to and outside of the deliverychamber. With valves 31 a–31 g, 31 i and 32 closed, and valves 31 b and31 h opened, IV solution is forced from the delivery chamber 27 to themixing chamber 28 by the control unit applying a positive pressure tothe delivery chamber's membrane and/or a negative pressure to the mixingchamber's membrane. The volume of liquid delivered to the mixing chambermay be determined by taking another measurement of the volume of airdefined by the control unit adjacent to and outside of the deliverychamber. Subtracting the volume of air measured before any liquid hasbeen delivered to the mixing chamber 28 from the volume of air measuredafter the liquid has been delivered to the mixing chamber provides thevolume of liquid delivered to the mixing chamber.

In order to introduce more IV solution into the mixing chamber, valve 31h is closed again and valve 31 a opened to fill the delivery chamber 27again with IV solution. Valve 31 a is closed, a bubble-detection cycleis performed, and a measurement of the air volume is again taken. Thenvalve 31 h is opened again, and IV solution is forced from the deliverychamber 27 to the mixing chamber 28. Another measurement of the airvolume is taken in order to determine the volume of additional IVsolution delivered to the mixing chamber. This cycle is repeated asoften as necessary to introduce the correct amount of IV solution intothe mixing chamber 28.

Once the mixing chamber 28 is filled with the desired amount of IVsolution, the process of reconstituting the powdered drug may begin. Inorder to reconstitute the drug in vial 11 a, valves 31 d and 31 i areopened, with all the other valves 31 a–31 c and 31 e–31 h kept closed.The control unit applies pressures to the membrane of the mixing chamber28 to force the IV solution therein into the vial 11 a.

Since the pressure within the vial often varies from the ambient (eitherbeing positively pressurized or having a partial vacuum), it is oftendesirable to check the pressure within the vial before thereconstitution process begins. It may be difficult to generate enough ofa pressure differential between the mixing chamber 28 and the vial 11 ato create a sufficiently strong spray to reconstitute the powdered drug,if the vial is positively pressurized. Since, it is usually preferableto bring the vial down to ambient pressure before the reconstitutionprocess begins, it is preferred to check the vial pressure before themixing chamber 28 is filled with IV solution. In order to check whetherthe vial 11 a is positively pressurized, valves 31 d and 31 h areopened, with all the other valves 31 a–31 c, 31 e–g and 31 i keptclosed; the mixing chamber 28 is kept substantially empty. If the vial11 a is positively pressurized, air escapes from the vial 11 a into themixing chamber 28. The control unit preferable includes a pressuretransducer that measures the pressure of the mixing chamber 28 (as wellas a pressure transducer that measures the pressure of the deliverychamber 27). The control unit measures whether there is an increase inthe pressure of the mixing chamber 28; the presence and size of apressure increase indicates whether and how much the vial 11 a ispressurized. By applying a negative pressure against the mixingchamber's membrane additional air may be removed from the vial 1 a tothe mixing chamber 28, so as to bring the vial 11 a to ambient. Themixing chamber 28 may be able to hold the excess air from the vial 11 aalong with the amount of IV solution necessary to reconstitute the drugin the vial 11 a, or if there is too much excess air it may be forcedfrom the mixing chamber 28 through valve 311 to the IV solution source(through port 22) or to the air vent 24 (if it is capable of venting airin two directions)—or even to another vial 11 b or 11 c if it hasalready been emptied.

If the vial 11 a has a partial vacuum, the partial vacuum does not ofcourse interfere with the delivery of IV solution from the mixingchamber 28 to the vial 11 a. A partial vacuum may, however, interferewith the drawing of liquid from the vial back to the mix chamber. Inorder to eliminate a partial vacuum, air may be drawn from vent 24 intothe vial 11 a. One way to determine whether a partial vacuum exists invial 11 a is to fill the delivery chamber 27 with air (from the vent 24)and then, after valve 31 g to the vent 24 is closed, opening valve 31 dto permit fluid communication between the delivery chamber 27 and thevial 11 a. The pressure in the delivery chamber 27 drops if the vial 11a has a partial vacuum. It is preferred that the vial be tested firstfor positive pressurization before being tested for a partial vacuum, sothat if there is positive pressurization no powdered drug isaccidentally blown into the delivery chamber 27, but rather is blowninto the mixing chamber 28.

After the vial 11 a is brought to ambient pressure (if necessary) andafter the mixing chamber 28 is filled with the desired amount of IVsolution, IV solution is sprayed into the vial 11 a by the applicationof pressure by the control unit onto the mixing chamber's membrane. Inorder to ensure that the powdered drug is sufficiently mixed with the IVsolution, the liquid is drawn back from the vial 11 a into the mixingchamber 28, and then in a preferred embodiment, resprayed into the vial11 a. This process is repeated several times. Quickly sloshing theliquid back and forth between the vial 11 a and the mixing chamber helpsensure that the powdered drug in vial 11 a is fully dissolved by the IVsolution.

Air pressure in the vial is managed during the repeated agitation to themixing chamber by pulling and pushing air and fluid to and from thebottom and the top of the mixing chamber. Thus, flow into and out of themixing chamber 28 is controlled by two valves, an upper valve 31 h,which permits air to leave the mixing chamber before liquid leaves themixing chamber, and a lower valve 31 i, which permits liquid to leavethe mixing chamber before air leaves the mixing chamber. The top port,shown in FIG. 2 as item 47, is used to introduce liquid into the mixingchamber and is used to remove air from the mixing chamber. The top portis shaped in accordance with the valve shown in FIGS. 22–24 of U.S.application Ser. No. 08/478,065, so as to permit removal of any smallair bubbles that may otherwise tend to collect at the port. (The topport 49 of the delivery chamber 27 has a similar design, since airbubbles need to be removed from the delivery chamber as well.) Themixing chamber's top port 47 is designed to remove air from the mixingchamber, since air of course tends to collect in the upper portion ofthe chamber. The bottom port 48 is used to remove liquid from the mixingchamber 28, since liquid of course tends to collect in the bottomportion of the mixing chamber.

As can be seen in FIGS. 5 and 6, which respectively show top and rearviews of the back-plate component of the cassette, both the deliverychamber 27 and the mixing chamber 28 have channels formed into the rigidwalls thereof. The channel 57 in the delivery chamber 27 permits easierflow into, out of and through the delivery chamber 27 when the membraneis resting against or near the rigid wall. As can be seen in FIG. 6, theupper portion 59 of the mixing chamber's channel is narrower than thechannel's lower portion 58. The channel's lower portion 58 permitseasier flow of liquid out of the mixing chamber 28 when the membrane isresting against or near the chamber's rigid wall. The difference ingroove depth promotes the flow of air and liquid from the top and bottomof the chamber respectively while minimizing the total volume containedin the groove.

Once the powdered drug is completely reconstituted, it may be treated bythe system as a liquid drug, which may or may not be diluted.

After the drug has been thoroughly mixed by sloshing the liquid back andforth between the mixing chamber 28 and the vial 11 a, the drug is readyfor delivery to the patient. If no further dilution of the drug isrequired, boluses of the drug are urged—by air pressure created by thecontrol unit against the mixing chamber's membrane, or negative pressureapplied against the delivery chamber's membrane—from the mixing chamber28 to the delivery chamber 27. From the delivery chamber, these bolusesof drug are delivered through valve 32 and stopcock valve 33 to thepatient in the same manner described above for delivering straight IVsolution to the patient.

If dilution of the drug is required, smaller boluses of thereconstituted drug may be urged from the mixing chamber 28 to thedelivery chamber 27, into which additional IV solution may be introducedin the correct proportions from the IV solution source, in order tolower the concentration of the reconstituted drug. Once the drug in abolus is diluted to the desired level, the drug may be delivered to thepatient in the same manner described above. Each successive bolus isdiluted and delivered in this manner. The control unit tracks the volumeof drug delivered to the patient and the rate at which it wasadministered. Another method of diluting the drug is to introduce avolume of liquid from the IV fluid source into the mixing chamber to bemixed with the liquid drug.

If it is desired to supply to the patient only a fraction of the drug inthe vial, the unused portion of the reconstituted drug may be returnedto the vial 11 a.

When after providing several boluses of reconstituted drug to thedelivery chamber 27, and the mixing chamber 28 is substantially emptiedof the drug, any drug that may be in the manifold 45 or other passagewaymay be urged to the delivery chamber 27 by drawing air into the manifoldfrom the vent 24, so that substantially all of the drug may be deliveredto the patient before the next delivery cycle begins. In order to drawair in through the manifold 45, the air-vent valve 31 g is opened andthe delivery-chamber inlet valve 31 b is opened, while all the othervalves 31 a, 31 c–31 f, 31 h–31 i, 32 are closed. The control unitapplies a negative pressure to the membrane of the delivery chamber 27,so as to draw fluid through the manifold 45 into the delivery chamber.Air is thus drawn through the vent 24 to fill in after the drug beingpulled through the manifold 45 into the delivery chamber 27. In thetwo-chambered system, air is also preferably drawn through the mixingchamber 28, in order to remove remants of the drug from the mixingchamber.

There are stages in the delivery cycle during which if air has beendrawn into the delivery chamber 27, it is important to remove the airfrom the chamber 27 without removing any of the drug. (The acousticvolume measurement system, which is the preferred method used to measurethe amount of liquid in the delivery chamber, does not work well ifthere is any bubble in the liquid.) To accomplish the removal of the airwithout permitting more than a tiny amount of reconstituted drug toescape, the delivery chamber is pressurized a little (with respect tothe manifold) and valve 31 b is opened and closed quickly; the chamber27 is again checked for the presence of a bubble. These steps arerepeated until no more air is detected. By keeping the pressuredifferential across the valve 31 b relatively small and opening thevalve for only a very short period of time, only a tiny amount, if any,of reconstituted drug can escape from the delivery chamber 27. If thevalve is allowed to be only partially opened during this process, evenless reconstituted drug can escape. Alternatively, the air may be pushedinto the relatively small manifold volume to control how much isreleased.

Before beginning a new delivery cycle, it may be desirable to clean anysmall amounts of the first drug from the passageways 25 so that the twodrugs do not mix. This cleansing of the cassette's passageways may beaccomplished by drawing IV solution from the IV solution source andpassing the IV solution into and out of the delivery chamber 27 (wherethe amount of IV solution may be measured), through the manifold 45 andthrough the mixing chamber 28. The emptied vial may also be rinsed. Asufficient amount of IV solution should be introduced into the cassette17 at this point in order to dilute to a safe, negligible concentrationwhatever remnants of the drug remain in the cassette so that the IVsolution used to cleanse the cassette may be sent to the patient. Theamount of IV solution used should be enough to ensure that the cassetteis properly rinsed so that residue of the prior drug does not interactwith the next drug.

It may be desired to deliver to the patient additional straight IVsolution before delivering the next drug from vial 11 b. When it is timeto prepare and deliver the drug from vial 11 b, the drug is prepared anddelivered in the same manner as described above in connection withpreparing and delivering the drug from vial 11 a. After the drug fromvial 11 b has been prepared and delivered to the patient, and after thecassette is cleansed of any remnants of the drug from vial 11 b, thedrug from vial 11 c may in turn be prepared and delivered to thepatient.

Depending on the desired treatment, the liquid drug provided to thecassette through port 26 may be provided to the patient before, betweenor after the delivery of the drugs in the vials 11 a–11 c. The liquiddrug provided through port 26 of course does not have to reconstituted;it may however need to be diluted prior to delivery.

The above-described system may be used in a variety of ways. Forinstance, the vials may be accessed in different orders (for example,vial 11 b, then 11 c and then 11 a, or first vial 11 c, then 11 a andthen 11 b). A vial may contain a powdered drug, which may bereconstituted, then diluted and then delivered, or which may simply bereconstituted and delivered. A vial may also contain a liquid drug,which may likewise be diluted and delivered, or simply be deliveredstraight. A drug may also be provided through the luer port 26 to bediluted and delivered, or simply delivered. The luer port 26 may alsoprovide a second IV fluid for use in reconstitution and/or dilution.Providing a secondary IV fluid through luer port 26, as well as aprimary IV fluid through port 22, is an important feature if the vialsattached to the cassette contain drugs that require different types offluids to be reconstituted and/or diluted properly.

When the cassette 17 is removed from the control unit 15, the controlunit is no longer able to control the membrane-based valves 31 a–31 i,32 and the stopcock valve 33. Each membrane-based valve assumes an openposition if not being actuated by the control unit, and the stopcockvalve 33 remains in an open position, if it had been in an open positionwhen the cassette was removed from the control unit. Without the outletfree-flow-prevention valve 35 shown in FIGS. 2 and 3, concentrated drugcould be accidentally delivered at an excessively high flow rate to thepatient. Without the inlet free-flow-prevention valve 34 shown in FIGS.2 and 3, concentrated drug may make its way out of the inlet port 22 tothe IV solution source 13, thereby contaminating the IV solution sourceso that it cannot be safely used again. In addition, multiple drugs inthe cassette and/or vial can mix creating hazardous and uncontrolledsolutions.

The inlet and outlet free-flow-prevention valves 34 and 35 are acted onby actuators mounted in the control unit's door when the cassette 17 isremoved from the control unit 15. When the door is opened, theseactuators push the membranes of the free-flow-prevention valves 34 and35 into a closed position, and the membranes are shaped to remain in aclosed position permanently once they are actuated. Thus, the removal ofthe cassette from the control unit closes the two free-flow-preventionvalves 34 and 35 and prevents liquid from flowing from the cassette toeither the patient or the IV solution source.

FIGS. 7–10 show several views of a membrane used in a preferredembodiment of the free-flow-prevention valves 34 and 35 shown in FIGS. 2and 3. The membrane includes a central plug portion 72, a rib 76 formounting the membrane in the rigid cassette body, and a relatively thin,folded portion 74 that connects the plug portion 72 and the rib 76. Whenthe actuator pushes the exterior end 82 of the plug portion 72, theinterior end 83 of the plug portion is urged into the fluid passageway(which leads to either the cassette's IV solution inlet 22 or thecassette's liquid outlet 23). The folded portion 74 is folded further bythis action, such that the plug portion 72 is held in the closedposition blocking the fluid passageway.

Thus, removal of the cassette 17 from the control unit 15 causes thefree-flow-prevention valves 34, 35 to be closed in such a way that theycannot be easily opened, so that they are essentially permanentlyclosed. Thus, the cassette can no longer be used. If the cassette isre-inserted into the control unit, the control unit senses an occlusionupstream when it attempts to draw IV solution from the IV solutionsource, or it senses an occlusion downstream when it tries to deliverliquid to the patient. The control unit, in a preferred embodiment,sounds an alarm after several attempts are made to pump liquid into orout of the cassette. In an alternative embodiment, the cassette may beprovided, in addition to the free-flow-prevention valves, with abreak-away tab that is broken off by an actuator when the cassette isremoved from the control unit. When a cassette of this type is insertedinto the control unit, the control unit determines whether thebreak-away tab is present on the cassette. If such a tab is present, thecontrol unit proceeds as normal, checking for occlusions, etc. If thetab is missing, the control unit sounds an alarm indicating that thecassette has been used already, and a new cassette should be inserted.The break-away tab thus allows the control unit to avoid performingseveral occlusion checks if the cassette has already been used.

The control unit may also be programmed to sound alarms when otherpotentially dangerous situations occur, and the control unit preferablyincludes a keypad so that information regarding the desired drugdelivery cycles for a given patient may be entered into the system sothat the drugs may be prepared and delivered according the desiredcycles. Information regarding the patient may also be entered into orread by the control unit, as well as information regarding the medicalprovider who is entering the information. Information regarding theproper, safe dosage levels for various drugs may be programmed into thecontrol unit, so that if, for example, the medical provider attempts toenter a dosage level that is greater than what is normally permitted,the control unit sounds an alarm. The control unit may also beprogrammed to prevent the delivery of an unsafe dosage, or it may beprogrammed so that a medical provider with sufficient authority mayoverride the programmed maximum dosage levels.

In a preferred embodiment, the control unit is connected to ahospital-wide network, so that information in the control unit may beupdated easily. For instance, information regarding the patient, such asweight and drug allergies, may be entered into the hospital network atadmissions. When the patient is to be connected to thedrug-preparation-and-delivery system described hereinabove, thepatient's identification code may be entered into or read by the controlunit, and the control unit can then access the network so that thepatient's information is available to permit the control unit to soundan alarm if the patient's drug allergies or low weight could create adangerous situation based on the drugs that are to be delivered or drugdelivery cycles that are to be implemented. A list of dangerous druginteractions may be kept and updated by the pharmacy as well. All drugsprovided to the patient, including the drugs administered by thedrug-preparation-and-delivery system described hereinabove, as well asdrugs provided by traditional means, may be recorded in the hospitalnetwork, and the control unit may sound an alarm is a dangerousinteraction may occur. Likewise, proper dosage and delivery-cycleinformation may be kept and updated by the hospital's pharmacy, so as toprovide the framework for safe drug delivery. If the desired drugdelivery cycle entered into the control unit does not fall within thesafety framework, the control unit may sound an alarm.

The control unit may also store information regarding the drugsdelivered to the patient and the time frames of the deliveries. Thisinformation may be downloaded into the network, so that it is availablefor later review by a medical provider, and so that the patient (or thepatient's insurance company) may be properly billed for the drugs thatare actually delivered to the patient.

Although the invention has been described with reference to severalpreferred embodiments, it will be understood by one of ordinary skill inthe art that various modifications can be made without departing fromthe spirit and the scope of the invention, as set forth in the claimsherein below.

1. A method for preparing an intravenous drug in a vial, the methodcomprising: providing a disposable cassette having (i) a liquid inletfor receiving a supply of liquid, (ii) a first vial spike, (iii) asecond vial spike, (iv) a variable-volume mixing chamber, the mixingchamber, the first and second vial spikes, and the liquid inlet being influid communication with each other, and (v) a valve mechanism, whichmay be actuated to control flow between the mixing chamber, the vialreceptacles and the liquid inlet; attaching the supply of liquid to theliquid inlet; attaching a first vial containing a drug to the first vialspike; introducing liquid from the liquid supply into the mixingchamber; measuring and introducing a first volume of liquid from themixing chamber into the first vial; causing liquid to flow between thefirst vial and the mixing chamber; attaching a second vial containing adrug to the second vial spike; measuring and introducing a second volumeof liquid from the mixing chamber into the second vial; and causing theliquid to flow between the second vial and the mixing chamber.
 2. Themethod according to claim 1, further comprising: causing an additionalvolume of liquid to be mixed with at least one of the drugs so as tofurther dilute the drug.
 3. The method according to claim 2, wherein thecassette is provided with a variable-volume delivery chamber, andwherein the additional volume of liquid is mixed with the drug in thedelivery chamber.
 4. A method for preparing an intravenous drug in avial, the method comprising: providing a disposable cassette having (i)a liquid inlet, (ii) a vial receptacle, and (iii) a attaching a supplyof liquid to the liquid inlet; attaching the vial containing a powdereddrug to the vial receptacle; introducing a volume of liquid into thevial; and causing the liquid to flow between the vial and the chamber tomix the powdered drug with the volume of liquid, wherein the liquid iscaused to flow repeatedly back and forth between vial and the chamber.5. The method according to claim 4, further comprising: causing anadditional volume of liquid to be mixed with the drug so as to furtherdilute the drug.
 6. The method according to claim 5, wherein thecassette is provided with a delivery chamber, and wherein the additionalvolume of liquid is mixed with the drug in the delivery chamber.
 7. Amethod for preparing an intravenous drug in a vial, the methodcomprising: providing a disposable cassette having (i) a liquid inlet,(ii) a vial receptacle, (iii) a mixing chamber, and (iv) a deliverychamber in communication with an outlet port, and wherein both themixing chamber and the delivery chamber are in valved communication withthe inlet port; attaching a supply of liquid to the liquid inlet;attaching the vial containing the drug to the vial receptacle; measuringa volume of liquid in the delivery chamber; causing the volume of liquidto flow to the mixing chamber; introducing the volume of liquid into thevial; and causing the liquid to flow repeatedly back and forth betweenthe vial and the mixing chamber to create a mixture.
 8. The methodaccording to claim 7, further comprising: causing an additional volumeof liquid to be mixed with the drug so as to further dilute the drug. 9.The method according to claim 8, wherein the additional volume of liquidis mixed with the drug in the delivery chamber.